Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models
FLT3 internal tandem duplication (FLT3-ITD) mutations account for ~25% of adult acute myeloid leukemia cases and are associated with poor prognosis. Venetoclax, a selective BCL-2 inhibitor, has limited monotherapy activity in relapsed/refractory acute myeloid leukemia with no responses observed in a...
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| Published in: | Haematologica (Roma) Vol. 106; no. 4; pp. 1034 - 1046 |
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| Main Authors: | , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Italy
Fondazione Ferrata Storti
01.04.2021
Ferrata Storti Foundation |
| ISSN: | 0390-6078, 1592-8721, 1592-8721 |
| Online Access: | Get full text |
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| Summary: | FLT3 internal tandem duplication (FLT3-ITD) mutations account for ~25% of adult acute myeloid leukemia cases and are associated with poor prognosis. Venetoclax, a selective BCL-2 inhibitor, has limited monotherapy activity in relapsed/refractory acute myeloid leukemia with no responses observed in a small subset of FLT3-ITD+ patients. Further, FLT3-ITD mutations emerged at relapse following venetoclax monotherapy and combination therapy suggesting a potential mechanism of resistance. Therefore, we investigated the convergence of FLT3-ITD signaling on the BCL-2 family proteins and determined combination activity of venetoclax and FLT3-ITD inhibition in preclinical models. In vivo, venetoclax combined with quizartinib, a potent FLT3 inhibitor, showed greater anti-tumor efficacy and prolonged survival compared to monotherapies. In a patient-derived FLT3-ITD+ xenograft model, cotreatment with venetoclax and quizartinib at clinically relevant doses had greater anti-tumor activity in the tumor microenvironment compared to quizartinib or venetoclax alone. Use of selective BCL-2 family inhibitors further identified a role for BCL-2, BCL-XL and MCL-1 in mediating survival in FLT3-ITD+ cells in vivo and highlighted the need to target all three proteins for greatest anti-tumor activity. Assessment of these combinations in vitro revealed synergistic combination activity for quizartinib and venetoclax but not for quizartinib combined with BCL-XL or MCL-1 inhibition. FLT3-ITD inhibition was shown to indirectly target both BCL-XL and MCL-1 through modulation of protein expression, thereby priming cells toward BCL-2 dependence for survival. These data demonstrate that FLT3-ITD inhibition combined with venetoclax has impressive anti-tumor activity in FLT3-ITD+ acute myeloid leukemia preclinical models and provides strong mechanistic rational for clinical studies. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Disclosures Contributions RSM, QZ, RD, EFC, MD, NPS, MK, DS and EAL designed experiments and analyzed data; RSM, EAL, QZ, RD, VMK, AC, VM and JR performed experiments; RSM, MD, DS and EAL wrote the manuscript. All authors reviewed and edited the manuscript. Venetoclax is developed in collaboration between Genentech, Inc. and AbbVie. RSM, VM, EFC, MD, DS and EAL are current or former employees of Genentech, Inc.. NPS received research funding from Bristol-Myers Squibb. MK is a consultant for AbbVie, Genentech, F. Hoffman La-Roche; served as advisory board member for F. Hoffman La-Roche and AbbVie; holds shares from Reata Pharmaceuticals; honoraria from Amgen, Abbvie, Genentech; research funding from AbbVie, Genentech, Eli Lilly, Cellectis, Calithera, Stemline, Threshold, Flexus Biosciences, Novartis, Ablynx, Agios and Amgen. All other authors declare no conflicts of interest. |
| ISSN: | 0390-6078 1592-8721 1592-8721 |
| DOI: | 10.3324/haematol.2019.244020 |